OX40 ligand is inhibitory during the effector phase of crescentic glomerulonephritis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background. The functional relevance of OX40 ligand (OX40L) in the effector phase of crescentic glomerulonephritis (GN) is unknown. These studies defined the role of endogenous OX40L during the effector stage of murine crescentic GN. Methods. GN was induced by immunization with sheep globulin/adjuvant on Day 0 and injection of sheep anti-mouse glomerular basement membrane immunoglobulin (Ig) on Day 10. Rat IgG or neutralizing anti-OX40L antibody was administered on Days 10-18 and immune responses and renal injury assessed on Day 20. Results. Compared with naïve animals, OX40L was upregulated in the lymph nodes (LNs) and on leucocytes and resident non-immune cells in the kidneys of mice with GN. Inhibition of OX40L in GN augmented renal injury, as indicated by increased crescent formation, proteinuria and glomerular leucocyte accumulation. In line with increased injury, anti-OX40L treatment increased proliferation and decreased apoptosis of CD4 T cells in the LNs, without affecting LN CD4 cytokine production and CD8 T-cell responses. Blockade of OX40L decreased LN regulatory T-cell (Treg) proliferation, transforming growth factor β production and foxp3 expression. OX40L inhibition did not affect B cell expansion or circulating antibody levels. In the kidney, neutralization of OX40L augmented interferon Î 3 (IFN Î 3) expression by CD4 and CD8 T cells and shifted macrophage polarization towards the pro-inflammatory M1 phenotype. Conclusions. OX40L is protective during the effector phase of murine crescentic GN by reducing the expansion of CD4 T cells and enhancing Treg responses in the LNs, and by locally inhibiting T-cell IFN Î 3 production and pro-inflammatory macrophage phenotype in the kidney.

Original languageEnglish
Pages (from-to)429-441
Number of pages13
JournalNephrology Dialysis Transplantation
Volume34
Issue number3
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • crescentic glomerulonephritis
  • IFN Î3
  • macrophage polarization
  • OX40 ligand
  • regulatory T cells

Cite this

@article{11beb979c86c4bb9826aa668dcc2979e,
title = "OX40 ligand is inhibitory during the effector phase of crescentic glomerulonephritis",
abstract = "Background. The functional relevance of OX40 ligand (OX40L) in the effector phase of crescentic glomerulonephritis (GN) is unknown. These studies defined the role of endogenous OX40L during the effector stage of murine crescentic GN. Methods. GN was induced by immunization with sheep globulin/adjuvant on Day 0 and injection of sheep anti-mouse glomerular basement membrane immunoglobulin (Ig) on Day 10. Rat IgG or neutralizing anti-OX40L antibody was administered on Days 10-18 and immune responses and renal injury assessed on Day 20. Results. Compared with na{\"i}ve animals, OX40L was upregulated in the lymph nodes (LNs) and on leucocytes and resident non-immune cells in the kidneys of mice with GN. Inhibition of OX40L in GN augmented renal injury, as indicated by increased crescent formation, proteinuria and glomerular leucocyte accumulation. In line with increased injury, anti-OX40L treatment increased proliferation and decreased apoptosis of CD4 T cells in the LNs, without affecting LN CD4 cytokine production and CD8 T-cell responses. Blockade of OX40L decreased LN regulatory T-cell (Treg) proliferation, transforming growth factor β production and foxp3 expression. OX40L inhibition did not affect B cell expansion or circulating antibody levels. In the kidney, neutralization of OX40L augmented interferon {\^I} 3 (IFN {\^I} 3) expression by CD4 and CD8 T cells and shifted macrophage polarization towards the pro-inflammatory M1 phenotype. Conclusions. OX40L is protective during the effector phase of murine crescentic GN by reducing the expansion of CD4 T cells and enhancing Treg responses in the LNs, and by locally inhibiting T-cell IFN {\^I} 3 production and pro-inflammatory macrophage phenotype in the kidney.",
keywords = "crescentic glomerulonephritis, IFN {\^I}3, macrophage polarization, OX40 ligand, regulatory T cells",
author = "Dragana Odobasic and Ruth, {Amanda J.} and Virginie Oudin and Kitching, {A. Richard} and Holdsworth, {Stephen R.}",
year = "2019",
month = "3",
day = "1",
doi = "10.1093/ndt/gfy177",
language = "English",
volume = "34",
pages = "429--441",
journal = "Nephrology Dialysis Transplantation",
issn = "0931-0509",
publisher = "Oxford University Press, USA",
number = "3",

}

OX40 ligand is inhibitory during the effector phase of crescentic glomerulonephritis. / Odobasic, Dragana; Ruth, Amanda J.; Oudin, Virginie; Kitching, A. Richard; Holdsworth, Stephen R.

In: Nephrology Dialysis Transplantation, Vol. 34, No. 3, 01.03.2019, p. 429-441.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - OX40 ligand is inhibitory during the effector phase of crescentic glomerulonephritis

AU - Odobasic, Dragana

AU - Ruth, Amanda J.

AU - Oudin, Virginie

AU - Kitching, A. Richard

AU - Holdsworth, Stephen R.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Background. The functional relevance of OX40 ligand (OX40L) in the effector phase of crescentic glomerulonephritis (GN) is unknown. These studies defined the role of endogenous OX40L during the effector stage of murine crescentic GN. Methods. GN was induced by immunization with sheep globulin/adjuvant on Day 0 and injection of sheep anti-mouse glomerular basement membrane immunoglobulin (Ig) on Day 10. Rat IgG or neutralizing anti-OX40L antibody was administered on Days 10-18 and immune responses and renal injury assessed on Day 20. Results. Compared with naïve animals, OX40L was upregulated in the lymph nodes (LNs) and on leucocytes and resident non-immune cells in the kidneys of mice with GN. Inhibition of OX40L in GN augmented renal injury, as indicated by increased crescent formation, proteinuria and glomerular leucocyte accumulation. In line with increased injury, anti-OX40L treatment increased proliferation and decreased apoptosis of CD4 T cells in the LNs, without affecting LN CD4 cytokine production and CD8 T-cell responses. Blockade of OX40L decreased LN regulatory T-cell (Treg) proliferation, transforming growth factor β production and foxp3 expression. OX40L inhibition did not affect B cell expansion or circulating antibody levels. In the kidney, neutralization of OX40L augmented interferon Î 3 (IFN Î 3) expression by CD4 and CD8 T cells and shifted macrophage polarization towards the pro-inflammatory M1 phenotype. Conclusions. OX40L is protective during the effector phase of murine crescentic GN by reducing the expansion of CD4 T cells and enhancing Treg responses in the LNs, and by locally inhibiting T-cell IFN Î 3 production and pro-inflammatory macrophage phenotype in the kidney.

AB - Background. The functional relevance of OX40 ligand (OX40L) in the effector phase of crescentic glomerulonephritis (GN) is unknown. These studies defined the role of endogenous OX40L during the effector stage of murine crescentic GN. Methods. GN was induced by immunization with sheep globulin/adjuvant on Day 0 and injection of sheep anti-mouse glomerular basement membrane immunoglobulin (Ig) on Day 10. Rat IgG or neutralizing anti-OX40L antibody was administered on Days 10-18 and immune responses and renal injury assessed on Day 20. Results. Compared with naïve animals, OX40L was upregulated in the lymph nodes (LNs) and on leucocytes and resident non-immune cells in the kidneys of mice with GN. Inhibition of OX40L in GN augmented renal injury, as indicated by increased crescent formation, proteinuria and glomerular leucocyte accumulation. In line with increased injury, anti-OX40L treatment increased proliferation and decreased apoptosis of CD4 T cells in the LNs, without affecting LN CD4 cytokine production and CD8 T-cell responses. Blockade of OX40L decreased LN regulatory T-cell (Treg) proliferation, transforming growth factor β production and foxp3 expression. OX40L inhibition did not affect B cell expansion or circulating antibody levels. In the kidney, neutralization of OX40L augmented interferon Î 3 (IFN Î 3) expression by CD4 and CD8 T cells and shifted macrophage polarization towards the pro-inflammatory M1 phenotype. Conclusions. OX40L is protective during the effector phase of murine crescentic GN by reducing the expansion of CD4 T cells and enhancing Treg responses in the LNs, and by locally inhibiting T-cell IFN Î 3 production and pro-inflammatory macrophage phenotype in the kidney.

KW - crescentic glomerulonephritis

KW - IFN Î3

KW - macrophage polarization

KW - OX40 ligand

KW - regulatory T cells

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U2 - 10.1093/ndt/gfy177

DO - 10.1093/ndt/gfy177

M3 - Article

VL - 34

SP - 429

EP - 441

JO - Nephrology Dialysis Transplantation

JF - Nephrology Dialysis Transplantation

SN - 0931-0509

IS - 3

ER -